Flavor additives in tobacco products and e-cigarettes are familiar stimuli with 'incentive' properties - they have been paired with sweet tastes or caloric post-ingestive effects in the past. These additives are intended to increase self-administration of nicotine by increasing palatability; however, they may also interact with the potent 'reward-enhancing' effects of nicotine to promote acquisition of self-administration and compulsive use. The inclusion of flavors with conditioned rewarding properties may also promote neurochemical changes that are correlated with long-term use and dependence. The specific objectives of the proposed studies are to investigate whether these flavor additives promote harm by increasing the number of individuals who smoke or use e-cigarettes; to determine whether flavor additives promote the development of nicotine dependence using pre-clinical models that measure motivation to take the drug as well as taking the drug in the face of aversive consequences; and to determine whether inclusion of flavor additives in the nicotine self-administration paradigm increases levels of mesotelencephalic dopamine, a neurochemical change that may contribute to compulsive substance use and dependence. We predict that flavors with conditioned reinforcing properties (paired with sweeteners in the past) will promote acquisition of self-administration at low nicotine doses, will increase nicotine 'dependence', and will cause regionally specific increases in neural growth factors. This research will make a significant impact on public health as it may reveal an important feature of smoked tobacco and e-cigarettes that encourage experimentation, repeated use, and dependence. The project builds on pre-clinical self-administration with the important innovations of including flavor stimuli in te self- administration paradigm and specifically using stimuli that model flavor additives in tobacco and e-cigarettes (flavors with incentive motivational properties). The experiments will begin by 'conditioning' the additives (e.g., menthol and strawberry) with incentive properties by pairing them with a sweet reward. This models most flavor additives (e.g., menthol, licorice, cocoa) which are familiar to most individuals who smoke before they are ingested in tobacco or e-cigarette formulations (e.g., candy canes, mints, ice cream, etc.). The flavor will then be self-administered in its unsweetened form, orally, by licking at a sipper tube. Nicotine is self- administered intravenously in conjunction with oral flavor delivery. This models inclusion of flavor additives in tobacco and e-cigarettes, which do not include potent sweeteners. Based on our preliminary findings, we expect that these conditioned reinforcing flavors will 1) reduce the dose of nicotine needed to acquire self- administration and 2) increase the motivation to obtain nicotine 3) increase nicotine self-administration in the face of negative consequences and 4) increase levels of dopamine in mesotelencephalic regions in which synaptic plasticity is associated with drug self-administration and substance dependence. We anticipate that these studies will have broad impact on the nicotine self-administration paradigm and public health.